An Experimental Medicine Approach for the Mechanistic Understanding of Cocaine Use Disorder: Reinforcer Pathology

用于理解可卡因使用障碍机制的实验医学方法：强化病理学

• 批准号: 10661032
• 负责人: Warren K Bickel
• 金额: $ 70.95万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661032
• 关键词: Address; Anterior; Behavioral; Biological Models; Brain; Brain Mapping; Brain region; Bypass; Cocaine; Cocaine use disorder; Computer Models; Consumption; Cues; Data; Event; Exposure to; Foundations; Functional Magnetic Resonance Imaging; Future; Generations; Goals; Hippocampus; Individual; Intervention; Laboratories; Lateral; Length; Maps; Measures; Mediating; Medicine; Methods; Modeling; Neurocognitive; Outcome Measure; Participant; Pathology; Patient Self-Report; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Process; Public Health; Randomized; Research; Research Project Grants; Resistance; Role; Specific qualifier value; Stress; System; Testing; Thinking; Time; Translational Research; Urinalysis; Work; addiction; biobehavior; cocaine use; computational neuroscience; craving; discounting; efficacious intervention; experimental study; improved; innovation; insight; interest; multiple drug use; neural; neurobehavioral; neurofeedback; neuroimaging; novel; open innovation; predictive modeling; reinforcer; sex; theories; therapeutic target; therapy development

PROJECT SUMMARY Developing a new generation of interventions for cocaine use disorder (CUD) constitutes an important scientific gap and, if addressed, will open innovation opportunities. To address this gap, we employ the Experimental Medicine approach to mechanistically examine Reinforcer Pathology, an emerging novel framework for addiction, that may provide a principled foundation for intervention development. Reinforcer Pathology specifies that reinforcers are integrated over a temporal window, and the length of that window determines the relative value of different reinforcers. When the temporal window is short, reinforcers such as cocaine, which are brief, intense, and reliable, will have greater value. Conversely, as the temporal window lengthens, other more temporally extended reinforcers begin to have greater influence and cocaine valuation will decrease. The concept of Reinforcer Pathology identifies the temporal window, measured with delay discounting (i.e., the decline in the value of a reinforcer as a function of its delay), as a therapeutic target for CUD, and it permits target engagement via innovative interventions (e.g., episodic future thinking; EFT) to provide novel insights into cocaine valuation. This project uses multiple analytical levels (e.g., the behavioral laboratory, neuroimaging, and computational modeling) to quantify, predict, and modulate cocaine valuation among individuals with CUD. In Aim 1, we will examine manipulations that increase and decrease the temporal window in parallel to mechanistically test the Reinforcer Pathology framework. In Aim 1a, we will examine the effects of successive exposure to an intervention that increases the temporal window (EFT) on concomitant changes in cocaine valuation (demand and craving). In Aim 1b, we will examine the effects of a manipulation that decreases the temporal window (stress probes) after exposure to EFT on concomitant changes in cocaine valuation. Throughout Aim 1, neural activity associated with changes in the temporal window will also be examined. In Aim 2, we will use multi-voxel analyses of fMRI data to explore two independent sub-aims related to Reinforcer Pathology in CUD. First, in Aim 2a, we will build multivariate group regression models of fMRI delay discounting data in a subset of participants with CUD to predict discounting in an independent subset of participants. Second, in Aim 2b, we will use real-time fMRI neurofeedback to enhance participants’ ability to control their temporal window, and hence their ability to modulate delay discounting and cocaine valuation. In Aim 3, we will model the temporal window by computationally quantifying results from Aims 1 and 2 (Aim 3a), and connecting subjective value to brain regions of interest using computational neuroscience (Aim 3b). Together, the findings from this rigorous and innovative research project will improve our understanding of CUD and highlight potential novel and efficacious intervention strategies.

项目摘要 开发新一代的可卡因使用障碍干预措施（CUD）构成了重要的科学 差距，如果解决的话，将开放创新机会。为了解决这一差距，我们采用了实验 机械学检查辅助病理学的医学方法，这是一个新兴的新型框架 成瘾，这可能为干预开发提供了主要基础。增强病理规格 增强剂在临时窗口上集成，该窗口的长度决定了相对 不同增强剂的价值。当临时窗口短时，可卡因等增援部队很简短， 强烈而可靠的价值将具有更大的价值。相反，随着临时窗口的延长，其他 暂时扩展的增强剂开始产生更大的影响，可卡因价值将降低。这 增强病理学的概念可以识别临时窗口，并以延迟折现（即 增强剂的价值下降是其延迟的函数），作为CUD的治疗目标，并允许 通过创新干预措施（例如，情节的未来思维； eft）进行目标参与，以提供新颖的见解 可卡因值。该项目使用多个分析级别（例如，行为实验室，神经影像学和 计算建模），以量化，预测和调节CUD个体中的可卡因值。在 AIM 1，我们将检查与并行增加和减少临时窗口的操作 机械地测试增强病理框架。在AIM 1A中，我们将研究成功的效果 暴露于可卡因伴随变化的临时窗口（EFT）的干预措施 价值（需求和渴望）。在AIM 1B中，我们将研究一种操纵的效果，以减少 暴露于可卡因价值变化的EFT后，临时窗口（应力问题）。 在整个目标1中，还将检查与临时窗口变化相关的神经活动。目标 2，我们将使用fMRI数据的多素分析来探索两个与增强剂相关的独立子aims CUD中的病理学。首先，在AIM 2A中，我们将建立fMRI延迟折扣的多元组回归模型 在参与者的一部分中，数据可以预测参与者独立子集中的折扣。第二， 在AIM 2B中，我们将使用实时fMRI神经反馈来增强参与者控制其临时性的能力 窗口，从而调节延迟折现和可卡因价值的能力。在AIM 3中，我们将建模 通过计算量化目标1和2（目标3A）的临时窗口，并连接主观 使用计算神经科学对大脑感兴趣的大脑区域的价值（AIM 3B）。在一起，从中发现 严格而创新的研究项目将提高我们对CUD的理解，并突出潜在的小说 和有效的干预策略。